Study of phosphorylated ribosomal protein S6 (pS6) in the clinical outcomes of patients undergoing hepatectomy for metastatic colorectal cancer.

Abstract

Introduction: Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, with up to 50% of patients developing metastatic disease, predominantly involving the liver. Hepatectomy remains the gold standard for resectable hepatic metastases; however, recurrence rates remain high and reliable prognostic biomarkers are lacking. Phosphorylated ribosomal protein S6 (pS6), a surrogate marker of PI3K/AKT/mTORC1 pathway activation, has been implicated in tumor aggressiveness across multiple cancer types, but its prognostic role after hepatectomy for metastatic colorectal cancer (mCRC) has not been established.

Objective: To evaluate the prognostic impact of pS6 expression and other molecular markers (BRAF V600E, p53, CERBB2, MSH6, PMS2, FUS, and HSPA9) assessed by immunohistochemistry on tissue microarray (TMA) on the clinical outcomes of patients undergoing hepatectomy for metastatic colorectal cancer.

Materials and methods: A retrospective cohort study was conducted including 64 patients who underwent hepatectomy for mCRC between 2012 and 2022 at a high-complexity oncology center in Northeast Brazil. Molecular marker expression was evaluated by immunohistochemistry on TMA constructed from paraffin-embedded hepatic metastasis specimens. Disease-free survival (DFS) at 1, 3, and 5 years and overall survival (OS) were analyzed using Fisher's exact test, Kaplan-Meier curves, and Cox regression multivariate analysis.

Results: Median OS was 23 months (95% CI = 18.33-27.66). Among all molecular markers assessed, only pS6 positivity (20.7% of cases) showed a statistically significant association with worse DFS at 1 year (p = 0.032), 3 years (p = 0.038), and 5 years (p = 0.018). A significant association was also identified between pS6 positivity and FUS positivity (p = 0.014). In multivariate analysis for DFS, pS6 positivity was an independent predictor of recurrence at 3 years (HRa = 9.710; p = 0.028) and 5 years (HRa = 11.857; p = 0.018), as were postoperative complications at 3 years (HRa = 8.671; p = 0.014) and 5 years (HRa = 6.912; p = 0.029). For overall survival, three independent predictors of mortality were identified: adjuvant chemotherapy (HRa = 0.052; p < 0.001), absence of 1-year DFS (HRa = 3.641; p = 0.001), and pS6 positivity (HRa = 4.547; p = 0.001).

Conclusion: Median overall survival was 23 months, reflecting the high mortality burden of mCRC after hepatectomy. Among all molecular markers evaluated, pS6 was the only one independently associated with worse disease-free survival and higher mortality risk, consistent with its role as a surrogate marker of PI3K/AKT/mTORC1 pathway activation, though a direct causal relationship cannot be established from the present data. A significant association between pS6 and FUS positivity suggests a possible convergence of oncogenic pathways warranting further investigation. Postoperative complications were independent predictors of recurrence, and adjuvant chemotherapy was the strongest independent predictor of improved overall survival. Given the retrospective single-center design and limited sample size, these findings are hypothesis-generating and require prospective multicenter validation before clinical application.